CA1090356A - Cyclopentanones and their application for the synthesis of prostaglandins - Google Patents

Abstract

The present invention relates to novel chemical compounds and methods for their preparation. They are compounds of formula: (I) in which R1, R'1, R2, R'2, R3, R4 and R8 separately represent a hydrogen, halogen atom, a radical of aliphatic character, a free or protected hydroxy methyl radical or a cyano radical; R'2 can also be an aryl, cycloaliphatic radical or a free or protected hydroxy radical; R'1 and R'2 taken together can represent a double bond or a substituted or unsubstituted alkylene or alkenylene radical; R5 and R6 separately represent a radical of aliphatic character, or p? together an unsubstituted or substituted alkylene or alkenylene radical; R7 represents a hydrogen or halogen atom, a radical of aliphatic character, an aryl radical, substituted or unsubstituted cycloaliphatic, a terpene radical, a substituted silyl radical or a metal cation, as well as the amides and anhydrides of the acids correspondents. These compounds are useful in particular as intermediates in the synthesis of prostaglandins.

Description

~ 9 ~
..
The present invention relates to novel chemical compounds.
mics useful in particular as synthesis intermediates in the preparation of known or new prostaglandins.
Prostaglandins are a large family of substances remarkable for the variety of their biological actions ques in mammals and in particular in humans.
Although these compounds have been extracted from many tissues, organs or body fluids of mammals, the quan-tities thus extracted remain very weak, except for the ester prostaglandin A2 methyl extracted from Plexaura corals homomalla. Thus AJ Weinheimer et al. (Tetrahedron Letters, 5183 (1969)) reported that the corals of the Plexaura family homomalla, found in the Caribbean Sea, contains large quantities of prostaglandins of the PGA2 family including hydro-xyle in C-15 has the absolute configuration (R). WOP. Schneider et al. (J. Amer. Chem. Soc., 94, 2122 (1972)), and A. Prince et al.
(Prostaglandins, 3, 531 (1973)) have reported that certain forms of Plexaura homomalla contain prostaglandins A2 of which the absolute configuration of C-15 hydroxyl is (S), that is, say identical to that of prostaglandins present in mam-mi ~ er.
Recent research has therefore aimed to achieve to a chemical synthesis of prostaglandins which would allow produce these compounds in sufficient quantity to be commercially readable in good conditions. (See for example: Tetrahe-dron Letters, 2093 (1967); J. Amer. Chem. Soc., 90, 3245 (1968);
91, 5364 (1969); 91, 5675 (1969); 92, 2586 (1970); 93, 1489 (1971);
93, 5594 (1971); 94, 4342, 4343 (1972); 95, 1676 (1973); 95, 6853 (1973); 96, 6774 (1974); 97, 857, 865 (1975)).

However, the total syntheses proposed in the prior techniques require a large number of stages of synthesis (in the order of 20 to 25 steps). We therefore understand that - 1 - L'`- .a even with good partial yields, the overall yield of these synth ~ its remains very weak, so we commonly get ren-overall values very less than 1%.
It is therefore interesting to offer a summary of the prostaglandins which requires a small number of stages (from the dre dlune tens), because independently of the improvement in generally as expected, this leads to a gain of time in the synthesis which constitutes a considerable advantage of the industrial point of view.
The present invention therefore provides new compos ~ s intended in particular to serve as a basis for the synthesis of prostaglan-dines as part of a fairly quick process, which by its flexible also allows itself to prepare new prostaglandins in excellent conditions.
The present invention also relates to methods for the preparation of these new compounds.
Finally, the invention relates to the application of these compounds.
sés to the synthesis of prostaglandins.
It may be useful to remember that prostaglandins belong to a fatty acid group with 20 carbon atoms pre-feeling a bond between the carbons in position 8 and in posi-tion 12 thus forming a cyclopentane radical having two variously unsaturated contiguous aliphatic chains.
The numbering of prostaglandins derives from the skeleton prostanic acid which has the following structure:

COOH
Y ~

<~ D1.

The following reviews give the definition of prosta-natural glandins and discuss their main activities:

1 ~ 903 ~
US von Euler and R. Eliasson (ed.), "Prostaglandins", Academic Press, London (1967); S. Bergstrom, Recent Progress in Hormone Research, 22, 153 (1966); Science, 157, 382 (1967); P. Ramwell and JE ~ Shaw (ed.), "Prostaglandin", Ann. NY Acad. Sci., 180, pp. 1-568 (1971); PW Ramwell (ed.), "The Prostaglandins", Plenum Press, London (1973); JC Colbert in "Prostaglandins, Isolation and Synthesis ", Noyes Data Corp., London (1973);
B. Samuelsson and R. Paoletti, "Advances in Prostaglandin and Thromboxane Research ", Vol. 1 and 2, Raven Press, New York, (1976).
In what follows and in accordance with usage, we indicate ~ uera by dotted bonds the substituents in oc, that is i.e. the substituents located behind the plane defined by the cyclopentane cycle and by ~ the links corresponding to substituents in ~, i.e. substituents located in front the plan of the cyclopentanic cycle. The connections in sinuous lines ~) indicate that the substituent can be in the oc position or ~, as for the links in solid lines, they do not presume not the position of the substituent attached to it. The Dotted lines represent a possible double bond.
The present invention is particularly directed towards a process for the preparation of a compound of formula I

R '~ / - 1' COR7 R ~ \ C ~ OR 6 (I) in which R4 represents a hydrogen atom, a halogen atom, a aliphatic radical, a free methyl hydroxy radical or prot ~ g ~ or a cyano radical; R'2 represents hydrogen, alkyl, alkenyl, aryl or cycloaliphatic; R'l and R'2 taken together can ~ 903 ~

represent a double bond or R'l represents hydrogen; R5 and R6 represent s ~ par ~ ment a radical of aliphatic character, or taken together an unsubstituted alkylene or alkenylene radical ~
or substituted; R7 represents a hydrogen atom, a radical with aliphatic character, an aryl radical, cycloaliphatic sub-substituted or unsubstituted ~, a terpene radical, a silyl radical substituted or a metal cation as well as the amides and the an-hydrides of the corresponding acids, characterized in that llon performs the ozonolysis of the compound of formula II:
o ll / OR7 R '~ (He) ~. ~ 4 in which R'l ~ R12, R4 and R7 have the meanings given previously.
The present invention relates more particularly acetals derived from cyclopentan-2-one carboxylic acid from formula I:

o R8 R

R 1 C0R7 (I) R1 ~ C ~ OR6 R 2 R2 R3 Rl 5 in which Rl, R'l, R2, R12, R3, R4 and R8 represent sepa-radiate a hydrogen atom, a halogen atom, a radical with character aliphatic, a free or protected hydroxy methyl radical or a cyano radical;
R'2 can also be an aryl, cycloaliphatic radical or a free or protected hydroxy radical;

~,; ~

iO9035 ~

Rll and R'2 taken together can represent a double bond or an unsubstituted or unsubstituted alkyl ~ ne or alk ~ nyl ~ radical;
R5 and R6 represent separately a radical with character ~ re aliphati-that, or taken together an alkylene or alkenylene radical not sub-substituted or substituted;
represents a hydrogen atom, d ~ halog ~ ne, a radical ~
aliphatic character, a radical aryl, cycloaliphatic substi-killed or unsubstituted, a terpene radical, a silyl radical sub-stitué or a metal cation, as well as the amides and anhydrides of the corresponding acids.
By radical with an aliphatic character is meant a radical cal of which the bonding carbon atom is not a part of a cycle. Among these radicals, we must cite very particular-aliphatic radicals: alkyl, alkenyl radicals, alkynyls, araliphatic radicals, in particular radicals aralkyl cals and (cycloaliphatic) -aliphatic radicals, in in particular the (cycloalkyl) -alkyl and (cyclo-alkenyl) -alkyl radicals.
Among the alkyl radicals mentioned above cédemment, it is necessary to quote very particularly the radicals alkyl-the lower ones, nor ~ or branched having less than 10 carbon atoms and, preferably ~ 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl radicals or terbutyle.
Likewise, the alkenyl radicals are preferably lower alkenyl radicals, normal or branched, mono- or di-unsatur ~ s having 2 to 10 carbon atoms, but preferably rence of 2 to 4 carbon atoms such as the vinyl radical.
Alkyl or alkenyl radicals can also be substituted by halogen atoms and are, for example mono-, di- or trifluoromethyl or mono-, di- or trichlo- radicals romethyl, or else these radicals can be substituted by various functions such as hydroxy, c ~ tone, etc ...

10903 ~;

Among the aryl radicals, mention should be made of any particular li ~ rement monocyclic radicals, such as the phenyl radical and ph ~ nyl radicals substituted by a ~ halogen atoms or hydroxy or alkyl groups.
Aralkyl radicals are preferably groups having in their arylated or alkylated portion the characteristics as mentioned above for the alkyl and aryl radicals such as the radical ben ~ yl.
The cycloalkyl and cycloalkenyl radicals comprise preferably 3 to 6 cha ~ nons such as cyclobutyl, cyclo-pentyl or cyclohexyl and are preferably the cyclo radical propyl or cyclopropylidene.
These cycloaliphatic radicals can be substituted by aliphatic radicals or be carried by car chains alky ~ ene or alc ~ nylene bonées described below.
Cycloalkylalkyl radicals are preferably titu ~ s in their cyclic part as has been said previously ment for cycloalkyl radicals and in their alkyl part as has been said for alkyl radicals.
Alkylene or alkenylene chains contain pre-ference between 2 and 5 carbon atoms such as ethylene chains, propyl ~ ne, butylene, ethenylene, propenylene or but-2- ~ nylene.
These chains can be substituted by alkyl radicals or can be bridged by alkylene or non-alkylene chains substituted ~ es or variously substituted.
Terpenic radicals are preferably ~ radicals menthyl, bornyle or isobornyle attached to a carbon atom conch of the radical.
Among the silyl radicals, mention should be made of any particular the trimethyl silyl radical in particular. Metal cations which are in question are more particularly cations pro-from alkali or alkaline earth metals such as sodium, D

~ (~ 903 ~ 6 potassium or calcium.
The hydroxy functions can be protected by one any of the methods known in particular by est ~ rification or eth ~ rification, est ~ rification taking place preferably ~ with carboxylic acids such as alkane carboxylic acids.
Halogens which may be present as a substitute kills are fluorine, bromine, chlorine and iodine but are of preferably chlorine.
The particularly interesting compounds of formula I
are the compounds of formula Ia:

~ ~ COOR7 (Ia) 1 ~ C ~ OR 6 / ~ OR ~
HO

variously substituted which are more specific intermediates usable in the synthesis of prostaglandins from E series and F series.
The compounds of formulas Ib and Ic:

G C00 ~ 7 ~ COOR ~

variously substituted s are also interesting compounds because they are intermediaries in the synthesis of prostaglan-dines of series A.
The present invention also relates to a process for the synthesis of the compounds of formula I by ozonolysis of the compounds ~ s D ~

1 ~ 903S ~

formula II:

R ~ ~ (II) R'2 R3 1 'R 1 ~ R2 ~ R 2 ~ R3 ~ R4, R7 and R8 have the meaning cation given for formula I.
This ozonolysis is preferably carried out in the presence low temperature ozone in a solvent to prepare for ozone nid, then reduction of the ozonide in a solvent in the presence of an-sulfur dioxide (see for example: R. De Master, Diss. Abst.
Int. B., 31, 5871 (1971)).
The solvent used in the stage of preparation of ozo-nest is preferably a mixture of chloride of m ~ thylene methanol and the reaction is carried out at -77C (for example in a mixture dry ice / acetone). The reduction of ozonide is ef-made by adding liquid sulfur dioxide and a solvent polar to the solution obtained previously. This polar solvent may be in particular an alcohol or a mixture of alcohol such as the methanol, ethanol or glycol. The use of anhydride sulfurous whose ~ boiling point is -10C, requires to operate at low temperature of the order of -20C. Sulfur dioxide preferably used is double-distilled sulfur dioxide.

Sulfur dioxide plays the role of ozonide reducer and catalyzes the formation of acetal.
The compound of formula II is pr ~ f ~ rence pr ~ prepared by one of the following:
a) From a compound of formula III:

~ ' lV9 ~ 3 ~

~ (III) in which R7 has the meaning given for formula I, by selective reduction of the double bond in position 3 of the 3,6-bicyclo [3,2,0 ~ heptadièn-2-one, in particular using hy-drogen in the presence of a selective catalyst, such as platinum, a compound of formula IIa is thus obtained in which R'l and R'2 represent a hydrogen atom:

o H ~ ~ (IIa ~

and in which ~ has the meaning given for formula I.
b) From a compound of formula III given pr ~ cedem-ment by epoxidation of the double bond in position 3 (see A.
Guzman et al., Prostaglandins, 8, 85 (1974)), followed by a reduction-tion of the ~ poxide bond to obtain a compound IIb of formula:

o ~ ~ OR7 H ~ (IIb) HO

in which R7 has the meaning given for formula I, the hydroxy radical which can be protected by any of the pro-known ceded, as is ~ rification. Epoxidation is conducted preferably in the presence of oxygenated water in an alkaline medium, in ..!

1 ~ 903: ~

a solvent such as methanol, ~ cold at a temperature of around from -15 to -20C, reduction of the ~ oxide is achieved ~ e selective-for example using aluminum amalgam in a soil before polar aprotic, such as dimethylformamide, under atmospheric inert sphere, for example under argon. The hydroxy function as well obtained is fixed in the oc position for steric reasons ~
c) From the compound of formula III, by the action of a diene compound conjugated to form a compound of formula IIc:

~ OR.7 ~ ~ (IIc) in which R7 has the meaning given for the formula I ~ En indeed, the double bond in position 3 of compound III is activated by the presence of the ketone group in oc and thus constitutes a dienophilic compound on which cycloadditions can be carried out 1.4 of Diels and Alder type; these reactions are well known, they can be conducted in an alcoholic solvent under conditions sweet. In particular, it can be reacted as a diene compound dim ~ thylfulvene, the compound ~ thus obtained is particularly interesting because it protects the double bond in position 3 of the cyclopentanone, which can be reconstituted at the end of the synthesis by a retro Diels and Alder type reaction by milking ment in diglyme, benzene, toluene or t ~ trahydrofu-ranne around 150 to 190C (see A. Ichihara et al., Tetrahedron Letters, 4231 (1974)).
d) From the compound of formula III, by reactions addition on the double bond of the addition type 1.4 of Michael, for example to fix alkyl radicals on the double bond by the action of alkyl lithium, 1,3-dipole additions or ,. ~

~ I ~ 3 ~

photochemical additions, such as that described by B. Graser-Reid et al., (Tetrahedron Letters, 297 (1975)), which allow to introduce substitutes on both sides of the double bond and lead to prostaglandins substituted ~ es in 10 and 11.
e) From the compound of formula III, by alkylation or halogenation of the positions located on either side of the ketone function by known methods.
Compounds of formula I can also be prepared from compounds of formula IV:

(IV) C ~ OR6 ~ OR5 in which R5. R6 and R7 have the meanings given for the formula I, by treating these compos ~ s in the same way as it was described for the compounds of formula III.
So the double bond of these compounds - can be hydrogenated, - may be subject to Michael type additions, additions dipole 1,3 or photochemical or, - Can be epoxy ~ e and reduced to fix a hydroxyl group.
Compound IV is like compound III a dienophile on which one can practice 1,4 cycloadditions of type Diels and Alder.
The same reaction sequences can be set work on compounds of formula III 'or IV' having already substitutions:

Dl ) 903 '~ 6 , 11 ~ OR7

2 F R4 ) ~ COOR7 R1 - \\ (IV ') in the formulas R1, R2, R3, R4, R5, R6, R7 and R8 have the meanings information given in formula I.
These compounds III, III ', IV, IV' can be prepared by methods which will be described below.
Some of the compounds of formula III and IIII are already ~
known and have already been prepared (see for example: WG Dauben et al., J. Amer. Chem. Soc., 85, 2616 (1963); KF Koch, Adv.
Alicycl. Chem. 257 (1967)).
They are preferably prepared by treatment of a derivative of oc-tropolone of formula V:

~ ~ OR7 ~ ~ (V) by irradiation.
The irradiation is preferably carried out in a soil vant such that methanol has a temperature close to 0C, ir-radiation being provided by a high-pressure ultra-violet lamp ~. ~

: 1 ~ 39 ~ 03S ~ d Hanau TQ 150 *. In order to ensure a return practically quantitative, it is essential to monitor the temperature and to use bidistilled m ~ thanol, the concentration of product V
must also be between 10 and 40 mM / l.
The tropolones of formula V are known or can be prepared for example by adding cyclopentadiene to the di-chlorocetene (HC Stevens et al., J. Amer. Chem. Soc., 87, 5257 (1965); L. Ghosez et al., Tetrahedron Letters, 135, (1966)), this which leads to a bicyclic compound of formula VI:
o (VI) Cl Cl This compound is transformed ~ into cc-tropolone by the Stevens method (see previous reference).
Then 11 ~ -tropolone obtained of formula Va;
o He oh ~ (Go) is etherified or ester ~ ied by conventional methods. For example-ple, C ~ C -tropolone can be m ~ thylated by the action of diazo-methane in methyl ether. (JW Cook et al., J. Chem. Soc., 503 (1951); WE Doering et al., J. Amer. Chem. Soc., 73, 828 (1951)).
The terpene ethers of 1 ~ e ~ C -tropolone have the advantage of leading to resolved products from the start of the synth ~ se, this is the case with ~ menthyl thers, borneol, isoborneol, for example. As for the ethers in which ~ re-has a halogenomic radical ~ thyl or trimethylsilyl, these pr ~ -feel that they are more labile and will lead to * Trademark ~ 1 ~

lvlsn3s6 compounds I advantageous for the synthesis of prostaglandins.
We also know of substituted tropolones of formula V ':

o R1 ~ ~ R7 R2 - ~) R8 (V ') R

in which the different substituents of tropolone have the meanings given in formula I and are in particular alkyl groups, halogen atoms or hydro-xymethyl or cyano (see the references cited above) or these are prepared by procedures ~ s similar to those described for compounds of formula V using substi- tute compounds you are. These compounds will lead to compounds of formula I sub-established by the same reaction sequences as those described previously.
We can illustrate a reaction scheme for the preparation tion of compounds I as follows:

V t ~

9t ~ 3 '~

= C = C / ~ ¢ ~ Cl (VI) ~ ~ 1 (Ya) ¢ ~ OR7 1 ~ (OB7 (III) R '~ (II) ~ ~ COOR7 R '~ C ~ OR6 R ~ 2 ~ OR;, (I) D

1 ~ 903 ~;

or alternatively from compound III:

OR7 ~ C; OR ~

(III) / (IV) ~ OR5 ~ COOR7 R'1 ~ ¦ (I) R'2 ~ 5 in these formulas, the substituents have the meanings given born for formula I, of course, the reaction sequence is the same starting from substituted Va or V compounds and we obtain compounds I having substituents R1, R2, R3, R4 and R8 different from hydrogen.
The products of formula I make it possible to prepare prostaglandins substituted in a variety of ways including by se-following reaction rate:

109 (~ 3t ~

) ~, C 2R7 ~ Hal [CH2] 6C02Alk (I) I ~ ~ OR6 ~ OR ~ /

O CO R o ) ~ LCH21 6 C2Alk ~ LCH21 6C2 C ~ R6 ~ OR6 ~ OR5 / ~ OR5 (VII) ~ / (YI II) OO
2r 215 2 O.- CH2 [CH215C02l11L
~ ZO ~ CH 2 D \ dd / C 5H 1 1 (IX) / (X) O

~ \ O ~ \ O
~ "- CH2 [CH2 ~ 5co2Alk ~ 'C ~ 2 [CH2l5c02 -\ J ~ CH2 ~ / C5H11 ~ CH2 ~ C5H ~ 1 (~ I) O / (XII) H OH
o ) ~, CH2 ~ CH2¦5C02H

CH2 '~ C5 OH

~,:
; ~

109 (V3 ~ ti In these formulas R5, ~ 6 and R7 have the meanings given for formula I, Hal represents a halogen atom and Alk a radical alkyl.
In this r ~ action diagram, for the sake of simplification, unsubstituted cyclopentane rings have been shown, heard the reaction sequences are the same starting from compounds of formula I having the substituents Rl, R'l ~ R2, R'2, R3, R4 and R8.
In order to simplify the nomenclature, the atoms of bone pentanic cycles will be numbered as shown for prostanic acid.
The compound of formula I is transformed into diester VII by an alkylation followed by the addition of a corresponding halide to the aliphatic chain that we want to fix in po-sition 8 of prostaglandin. In this case, in order to pr ~ -adorn a natural prostaglandin, the fix compound ~ is the ester heptyl iodide-7 ethyl alcohol.
The alkylation in position 8 of compound VII is carried out in the presence of potassium hydride in dimethyl sulfoxide an-hydra (DM Pond et al., J. Org. Chem., 32, 4064 (1967); CA
Brown, JO Org. Chem., 39, 3913 (1974)), then add the ester ~ thylic pr ~ previous pr ~ ready for example from tetrahydro-pyran (MoE. Synerholm, J. Amer. Chem. Soc., 69, 2581 (1947);
DE Ames et al., J. Chem. Soc., 174, (1950)) O
The diester VII thus obtained is decarboxyl ~ to obtain Compound VIII by treatment with potassium cyanide in the hexamethylphosphoric acid triamide (HMPT) (P. Muller et al., Tetrahedron Letters, 3565 (1973)).
Acetal VIII is transformed into an aldehyde of formula IX
by acid treatment.

The aldehyde IX is then alkylated to give the compound of formula X, either by treatment with dimethyloxo-2-phosphonate i ~ 9035 ~;

heptyl in dimethoxym ~ thane in the presence of sodium hydride (EJ Corey et al., J. Amer. Chem. Soc., 91, 5675 (1969); 92, 397 (1970); 93, 1491 (1971)), either by regional aldolic condensation specific for kinetic lithium enolate gen ~ r ~ from m ~ thyl-pentyl-c ~ tone (G. Stork et al ~, J. Or ~. Chem., 39, 3459 (1974)).
The ~ none of formula X is transformed into monoc ~ tal of formula XI by treatment with ethylene glycol in the presence of a trace of p-toluene sulfonic acid.
The reduction of the carbonyl function in position 15 of the compound XI is produced either with sodium borohydride or with zinc borohydride (P. Crabbé et al., J. Chem. Soc. Perkin I, 810 (1973)) and leads to a mixture of alcohol in 150C and 15 ~, which are separated by preparative chromatography on silica gel.
Acid hydrolysis of the compound of formula XII having the alcohol function in position 15 d regenerates the keton function that in position 9, then the alkaline hydrolysis in position 1 leads to the ll-d ~ hydroxy PGEl.
Of course, starting from a compound ~ in which R ' and R'2 represent a double bond as composed by Ib on would have obtained prostaglandin Al in the same way.
Starting from a compound ~ Ic and at the end of the reaction in practicing a Diels and Alder retro reaction, we also obtain a prostaglandin A1.
Starting from a compound in which Rl2 is a function hydroxyl that we would have taken care to protect, for example by esterification, we would have obtained a prostaglandin of the El type in lib ~ rant hydroxyl function.
Although in this sch ~ my reaction we started ~ by fix the chain in position 8, it is possible by following same reaction sequences to start by fixing the chain in position 12 ,, . ~., ~

903 ~ 6 One of the advantages of this synthesis, besides the fact that it is fast, is to allow the preparation of prostaglan-dines carrying various substituents in position 8, 10, 11 and 12 starting from a suitable compound of formula I and furthermore it is possible to fix in position 8 chains of va-laughed, especially cats with several unsaturated or chains containing 1,2 cyclopropylene radicals or cyclopropyl-1-ylidene-2 or, for example, radicals of the furan type, t ~ trahydrofuran, pyranne variously substituted.
But from the compounds of formula I, it is possible also to synthesize prostaglandins by another scheme reaction illustrated below:

DR6 ~ C OR

(I) / (XIII) OR OR ~

G ~ OR D ~ onS

(XIV) / (XV) GOLD
~ (C ~ 2) 6C02 t <~ 1 C ~ OR6 ~ OR5 (XVI) ,. ~, i, l ~ J9035 ~;

in these formulas R5, R6 and ~ 7 have the meanings given for formula I and Rg is a protective radical of the function hydroxy, for example an alkyl group, and Et is the ethyl radical.
Compound I is trans ~ orm ~ into a mixture of alcohol position 9 of formula XIIIa by reduction of the carbonyl function in position 9.
The alcohol function of compound XIIIa is protected by etherification to form the compound of formula XIII.
Compound XIII is transformed ~ into compound ~ XIV by reduction of the ester in position 8 in the presence of dihydride isobutyl aluminum in toluene at -70C (LI Zakharkin et al., Tetrahedron Letters, 619 (1962)).
Aldehyde XIV is transformed into compound XV by r ~ ac-tion of sodium salt, triph ~ nylphosphoniohexanoic acid in anhydrous dimethylsulfoxide.
Compound XV is transformed into compound ~ XVI pr ~ cur-of prostaglandins of series 1 by catalytic reduction.
The chain in position 12 is fixed in the same way as previously described for the compound of formula ~ III
the only difference is that you don't have to go through through a type XI compound, since the function in position 9 is already protected. We will thus obtain a compound 11-d ~ hydroxy PGFl. As has been said above, we can obtain by the same sch ~ my reaction of many other prostaglandins, in particular prostaglandin F1.
To prepare series 2 prostaglandins, you can operate according to the following reaction scheme:

D.

109103 ~

CHO ~ CH = CH - S <

6 ~ OR6 ~ OR5 ~ OR5 (XIV) / (Y, YII) ORg ORg CH2-CHO ~ C ~; 2 ~ = / C3H6C2 ~ t D <
~ R6 - ~ C --- OR6 ~ OR5 ~ OR5 ~ XVIII) (XIX) Starting from compound XIV, compound XYII is prepared by treatment with triphenyl-phosphoranilidene-phenylmercapto-methane in dimethyl sulfoxide, which leads to a mixture of cis- and transthio ~ thervinyle (N. Finch et al., J. Org. Chem., 38, 4412 (1973)).
Reaction of product XVII with mercuric acetate in acetonitrile followed by the reductive cleavage of the ad-organomercuric edition with aluminum amalgam in tetrahy-drofuran and the hydrolysis of acetoxyphenylmercaptoacetal with potassium carbonate in methanol leads to aldehyde XVIII.
Treatment of compound XVIII with the sodium salt of triph ~ nylphosphoniopentanoic acid in dim ~ thylsulfoxide ~. ~

~ 035 ~ i anhydrous leads to compound XIX pr ~ cursor prostaglandins of series 2 (I. Vlattas et al, Tetrahedron Letters, 4451, (1974)), which can be treated as previously stated.
Although in the two previous reaction schemes we started by fixing the chain in position 8, it is possible perform the same reaction sequence starting with fix the chain in position 12.
The examples below are intended to illustrate some modes of implementing the process according to the present invention, but do not constitute a limitation.
Example 1 To a solution of Z0 ml of 30% sodium hydroxide and 15 ml diethylene glycol monomethyl ether, kept at 0, we add 100 ml of ether, then 6 g of bis (N-methyl N-nitroso) tere-phthalamide (with magnetic stirring). We maintain at 0 ~ (bath ice) and distill the diazomethane into a container containing ether. The diazomethane solution is added to a solution of 50 ml of ether containing 1.25 g of o ~ -tropolone (Va).
The reaction mixture is kept for one hour at 0, then 2 hours ~ ordinary temperature. Excess diazomethane is destroyed by a few drops of acetigue acid ~ The ether is evaporated under vacuum, ~ dropping the methyl ether of 1 'c ~ c -tropolone (V) ~
Example 2 A solution containing 0.9 g of methyl ether 1 'C ~ c -tropolone (V) in 240 ml of redistilled and anhydrous methanol is cooled ~ 0 and stored ~ e under an argon atmosphere. This solution is irradiated by a high pressure ultraviolet lamp Hanau TQ 150 to 0 for 6 hours. The solvent is removed with rotavapor under reduced pressure. The oily residue is distilled under high vacuum E ~ 80 giving the 7-m ~ thoxy-3,6-bicyclo C3,2,0]
heptadiene-2-one (III).

~., 1 (~ 903S6 Example 3 80 mg of platinum oxide are added to 30 ml of acetate distilled ethyl. After ~ evacuation of the air, we place in atmos-hydrogen sphere and reduces the platinum catalyst. We dissolve 580 mg of the compound of Example 2 (III) in 75 ml of acetate distilled ethyl and added perhydrogenated platinum. The mixture is hydrogenated ~ at ordinary pressure and temperature ~ ambient temperature up to ~
absorption of hydrogen corresponding to a ~ equivalent. After ~
sorption, the catalyst is filtered, the solvent is evaporated with rotava-fear and distill the product under vacuum ~ 60. This gives le7-methoxy-6-bicyclo ~ 3,2, ~ heptene-2-one (IIa): liquid inco-lore, ~ max 3070, 1730 and 1625 cm 1, NMR 4.75 (s, vinyl H),

3.60 ppm (s, Me).
Example 4 5.7 ml of methanol are added ~ a solution containing 1.62 g of the compound of Example 3 in 29 ml of methyl chloride l ~ ne. The mixture is cooled to -77 (C02 ~ ac ~ tone) and the solution cooled ~ a stream of dry ozone. After a few minutes your appears a slight blue coloring. We dissipate it by step-wise with a stream of dry argon for a few seconds. To the solution thus obtained, 2 ml of sulfur dioxide are added per distillation (-10). After 5 minutes ~ -77, 4 hours at -20, one hour at 0 and one hour at room temperature, evaporated solvents under vacuum, rotavapor and extraction according to the usual technique, we obtain the methyl ester of acid 5-(dimethoxy methyl ~ -cyclopentan-2-on-1-o'ique; colorless oil, ~ max 1750 - 1730 cm, RM ~ N. 4.25 (d, J = 5 Hz, acetal H), 3.70 (s, Me ester), 3.35 p ~ pm (d, J = 1.5 Hz, 2 X OME), FeC13 test:
positive.
Example 5 We operate as in Example 4 starting from the compound ~ of Example 2, 7-m ~ thoxy-3,6-bicyclo ~ 3,2,0] heptadiene-2-one, :

losn3 ~

we get the met ~ ylique acid 5- (dimethoxymethyl) -cyclopent-3-en-2-on-1-oique.
Example 6 To a solution of lithium dimethyl copper prepared at from 950 mg of copper iodide in 20 ml of anhydrous ether, cooled to -10, a solution of methane is added dropwise thyllithium 2 molar, under argon, until discoloration. We add this solution drop by drop ~ 220 mg of cyclopenter none obtained in Example 5 in 15 ml of anhydrous ether, in con-serving the temperature between -20 and -25 for 15 minutes. We then add an aqueous solution of ammonium chloride and add one hour at room temperature. We extract at ~ ther, wash and dry over anhydrous sodium sulfate. We filter, evaporate the solvent under vacuum and chromatography on 25 g of Florisil. We thus isolates the methyl ester of acid 5- (dim ~ thoxy m ~ thyl) -

4 ~ methyl cyclopentan-2-on-1-oic. Using as a product of reaction the compound of example 5 and ~ thyl lithium is obtained 5- (dimethoxy methyl) -4- ~ thyl cyclo- acid methyl ester pentan-2-on-1-oique. Using as reaction product the compos ~ of Example 5 and vinyl lithium we obtain the ester 5- (dim ~ thoxy methyl) -4-vinyl cyclopentan-2- methyl on-l-olque. Using as a reaction product the compound of Example 5 and cyclopropylithium, the methyl ester is obtained 5- (dimethoxy methyl) -4-cyclopropyl cyclopentan-2-on-1- acid o ~ that. Using as a reaction product the compound of example 5 and butyllithium we obtain the methyl ester of 5- (dimetho ~ y methyl) -4-butyl-cyclopentan-2-on-1-oic acid. ~ n using as reaction product the compound of Example 5 and phenyllithium we get the methyl ester of acid 5-(dimethoxy methyl) -4-phenyl cyclopentan-2-on-1-o; que.
Example 7 Treatment of 10 g of tetrahydropyran with . . ~, acetyl chloride at reflux in anhydrous benzene, in the presence of zinc chloride provides the methyl alcohol ester 5-chloropentylic ~ The reaction of this chlor ~ derivative with malo-~ ethyl nate, in the presence of sodium and sodium iodide, a reflux in ethyl alcohol, gives the acid ester lactone ~ J-hydroxy-heptanoic. This is converted to an ester ~ thyli-only bromo-7-heptano acid ~ only by treatment with bromic acid-water and sulfuric acid in solution in acetic acid.
The ethyl ester of bromo-7-heptanoic acid is converted into iodo-7-heptanoic derivative by r ~ action with sodium iodide in anhydrous acetone, 2 h at room temperature.
Example 8 328 mg of the keto-ester are quickly added under argon obtained in Example 4, in solution in 3 ml of dim ~ thylsulfoxide anhydrous (distilled over calcium hydride) to an oil dispersion 75 mg of potassium hydride (330 mg of 22.5% mixture;
1.8 mml). After stirring at room temperature for 15 minutes (cessation of the ~ evolution of hydrogen), 900 mg are added of the compound obtained pure in Example 7 and the reaction mixture is stirred for 27 h at ordinary temperature. We then pour into a water-hexane mixture, extracted with hexane, dried over sulphate anhydrous sodium, filters and obtains the diester after chromatography of formula VII in which R5, R6 and R7 represent the radical methyl and Alk the ethyl radical: oil, ~ max 1745 - 1730 cm NMR ca. 4.12, 4.16 (acetal H), 3.95 (q, J - 7 H ~, CH2Me), 3.55 (s, Me ester), 3.25 (s, OMe), 1.20 ppm (t, J = 7 Hz, CH2Me); m / e 340 (M -MeOH).
Example 9 A mixture containing 37 mg (0.1 mml) of diester of Example 8, 10 mg of cyanide sodium (0.2 mml) and 1 ml of hexamethyl phosphotriamide (redistill ~ e on sodium) at 75 for 1 hour 1/4, then overnight ~ temperature D

10 ~ 03S ~

ordinary. Then added, under a hood, the reaction mixture has a mixture of 10% hydrochloric acid in water and hexane.
Then extracted and dried over sodium sulfate and carbonate potassium. After filtration and evaporation of the solvents under empty, the mono-ester of formula VIII is obtained in which R5 and R6 represent the methyl radical and Al ~ the ethyl radical:
liquid, ~ max 1730 cm 1; NMR ca. 4.12, 4.16 (ac ~ tal H), 4.05 (q, ~ Hz, CH2Me), 3.35 (s, 2 X OMe); 1.2 ppm (t, J = 7 Hz, CH2Me).
Example 10 A solution containing 50 mg of the acetal of the monoester obtained ~ Example 9 in 4 ml of acetone and 4 mg of acid p-toluenesulfonic monohydrate, for 62 h at room temperature, under argon. Thrown into water, extracted with ether, washed with of a bicarbonate solution, dried over sodium sulfate, filtered, and evaporates under vacuum. The aldehyde of formula IX is thus isolated in pure form.
Example 11 368 mg of dimethyl oxo-2- are stirred under dry argon heptyl phosphonate (1.65 mml) in 10 ml of dim ~ thoxyethane (redistill ~ on double hydride of lithium and aluminum), to which 68 mg of sodium hydride are added (55-60% oily solution;
1.65 mml) in 11 ml of dimethoxyethane. After an hour ambient temperature, the mixture is cooled to -15 and added quickly.
400 mg of the aldehyde of formula IX obtained in Example 10, in 6 ml of dim ~ thoxy ~ thane. After 2 1/2 hours between -10 and 0, the mixture is kept overnight at ordinary temperature. We add about 0.1 ml of acetic acid to dissolve the solids.
Then evaporated to dryness with a rotary evaporator, then chromatographed on a column of 60 g of silica gel, eluting with chloride methylene and ethyl acetate. We collect a light oil-ment purified ~ e by preparative chromatography on gel of -D
`, ~

1 (~ 903 ~;

silica. The enone of formula X is thus obtained in pure form.
Example 12 A solution containing 200 mg of ~ none of formula X obtained in Example 11 in 100 ml of anhydrous benzene, 25 ml of ethylene glycol and 10 mg of p-toluene sulfonic acid. We removes water by azeotropic distillation. We follow the reaction by chromatoplate and continues heating until reduced the intensity (molecular extinction coefficient) of the enone in ultra-violet. Cool, throw in water, wash with bi-sodium carbonate and extract with ethyl acetate. It is dried over sodium sulfate and the solvents are distilled under high vacuum.
The mono-ketal of formula XI is purified by preparative chromatography.
rative on silica plates.
Example 13 120 mg of the mono-ketal of formula XI obtained are dissolved in Example 12 in 20 ml of dim ~ thoxymethane distilled. We add a solution of borohydride of ~ inc in dimethoxy-ethane, prepared by reaction between sodium borohydride and zinc chloride. Leave to react for 2 hours at ordinary temperature.
Poured into water, extracted with ethyl acetate, washed and dried on anhydrous sodium sulfate. The solvents are filtered and evaporated under vacuum.
The mixture of alcohols of formula XII is separated by preparative thin layer chromatography on silica gel.
The (R) and (S) isomers are thus isolated in pure form.
Example 14 75 mg of the alcohol are treated in ~ obtained in Example 13 with a solution containing 5 mg of p-toluenesulfonic acid in

5 ml of acetone overnight at room temperature. Then we add an excess of sodium bicarbonate solution and ~ va-pore 4/5 of the volume. 10 ml of a solution are then added methanolic containing 200 mg of potassium carbonate and preserves ~. . .

~ L0903S6 overnight at room temperature to hydrolyze the ester to Cl.
The course of the reaction is followed by layer chromatography thin, and isolate ll-dehydroxy-PGEl.
References given in parentheses are intended to illustrate some analog processes.
Other prostaglandin preparation from the compounds of formula I are described in more detail in Patent application 2 ~ 1,341 filed on the same day by the Application-resse and having for title: "New processes of synthesis of prostaglandin derivatives ".

,,,, I

Claims (12)

The embodiments of the invention, about which an exclusive right of property or privilege is claimed, are defined as follows: 1. Process for the preparation of a compound of formula I

(I) in which R4 represents a hydrogen atom, halogen, an aliphatic radical, a hydroxy radical free or protected methyl or a cyano radical; R'2 represents hydro-gene, alkyl, alkenyl, aryl, or cycloaliphatic; R'1 and R'2 taken together can represent a double bond or R'1 represents hydrogen; R5 and R6 represent separately a radical with charac-aliphatic, or taken together an alkylene or alkenylene radical unsubstituted or substituted; R7 represents a hydrogen atom, a aliphatic radical, an aryl, cycloaliphatic radical substituted or unsubstituted, a terpene radical, a silyl radical substituted or a metal cation as well as the amides and the an-hydrides of the corresponding acids, characterized in that performs the ozonolysis of the compound of formula II:

(II) in which R'1, R'2, R4 and R7 have the meanings given previously. 2. Method according to claim 1, characterized in what ozonolysis is conducted in the presence of ozone in a solvent followed by ozonide reduction in the presence of anhy-sulphurous dride. 3. Method according to claim 2, characterized in what the solvent used is a mixture of methylene chloride and methanol and in that ozonide reduction is conducted in the presence of alcohol. 4. Method according to claim 1, characterized in that that a compound of formula I is prepared in which R4 is the hy-drogen and R5, R6 are methyl radicals by ozonolysis of corresponding compound of formula II in the presence of ozone in the methanol and reduction of ozonide with sulfur dioxide. 5. Method according to claim 1, characterized in that the compound of formula II is prepared in part from a com-set of formula III ':

(III ') in which R'2, R4 and R7 have the meanings given in claim 1 a) by selective reduction b) by adding 1.4 of Michael per share of a lithium di derivative (R'2) copper with the compound of formula III 'in which R'2 is hydrogen. 6. Method according to claim 5, characterized in what the selective reduction of the double bond in position 3 is carried out using hydrogen in the presence of platinum. 7 Method according to claim 6, characterized in what the Michael type 1.4 addition is achieved by action lithium di alcoyl copper, lithium di alcenyl copper, lithium di phenyl copper or lithium di cycloalkyl copper. 8. Method according to claim 5, characterized in that the compound of formula III 'is obtained by irradiation of a tropolone of formula V ':

(V ') in which R'2, R4 and R7 have the meanings given in the claim 5. 9. Method according to claim 8, characterized in that the irradiation is ensured by an ultra-violet lamp at high pressure Hanau TQ-150. 10. Method according to claim 8, characterized in what the compound of formula V:

(V) is prepared by reaction of cyclopentadiene with dichlorocetene and that the compound obtained is transformed into.alpha.-tropolone by the Stevens method, and then the compound obtained is etherified. 11. Process for the preparation of compound of formula I, in which R'2 represents an alkyl, alkenyl, acyl or cycloaliphatic, characterized in that a compound is reacted set of formula IV ':

(IV ') by addition 1,4 of Michael type with lithium di alkyl copper, lithium di alkenyl copper, lithium di aryl copper or lithium di copper cycloalkyl. 12. Compound of formula I:

(I) in which R4 represents a hydrogen atom, a halogen atom, a aliphatic radical, a free hydroxy methyl radical or protected or a cyano radical; R'2 represents hydrogen, alkyl, alkenyl, aryl or cycloaliphatic; R'1 and R'2 taken together can represent a double bond or R'1 represents hydrogen; R5 and R6 separately represent an aliphatic radical or, taken together an unsubstituted alkylene or alkenylene radical or substituted; R7 represents a hydrogen atom, a radical with aliphatic character, an aryl, substituted cycloaliphatic radical or unsubstituted, a terpene radical, a substituted silyl radical or a metal cation as well as the amides and anhydrides of corresponding acids when prepared by the claim process tion 1 or its obvious chemical equivalent.